jm0c00899_si_002.csv (3.79 kB)

Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase

Download (3.79 kB)
posted on 19.08.2020 by Noelle S. Williams, Stephen Gonzales, Jacinth Naidoo, Giomar Rivera-Cancel, Sukesh Voruganti, Prema Mallipeddi, Panayotis C. Theodoropoulos, Sophie Geboers, Hong Chen, Francisco Ortiz, Bruce Posner, Deepak Nijhawan, Joseph M. Ready
A series of N-acyl benzothiazoles shows selective and potent cytotoxicity against cancer cell lines expressing cytochrome P450 4F11. A prodrug form is metabolized by cancer cells into an active inhibitor of stearoyl-CoA desaturase (SCD). Substantial variation on the acyl portion of the inhibitors allowed the identification of (R)-27, which balanced potency, solubility, and lipophilicity to allow proof-of-concept studies in mice. The prodrugs were activated inside the tumor, where they can arrest tumor growth. Together, these observations offer promise that a tumor-activated prodrug strategy might exploit the essentiality of SCD for tumor growth, while avoiding toxicity associated with systemic SCD inhibition.